Exposure to flame retardant chemicals has become a significant environmental health problem. Until 2004, polybrominated diphenyl ethers (PBDEs) were used as the primary flame retardant additive in furniture in the United States. Unfortunately, the high use of PBDEs led to significant human exposure issues, particularly for children. As a consequence, U.S. children have the highest body burdens of PBDEs in the world, and new data suggest that these exposures have contributed to neurodevelopmental problems, including reductions in psychomotor developmental indices, mental developmental indices, and even IQ. Furthermore, PBDEs are known to affect thyroid hormone regulation, which is intimately linked with neurodevelopment. A study by our laboratory has found that PBDE levels in pregnant women are significantly associated with increased circulating levels of maternal thyroid hormones, decreases in birth weight, and reductions in head circumference in infants. We hypothesize that this trend is driven by inhibition of the thyroid regulating deiodinases (DIs) which metabolize thyroid hormones within tissues. In vitro studies using human liver sub-cellular fractions have demonstrated that PBDE metabolites significantly reduce DI activity. In addition, in vivo exposures to PBDEs in fish models have resulted in significant decreases in basal DI activity. During pregnancy, DI activity in placenta tissues is essential in regulating the supply of active thyroid hormones to the developing fetus. Knock-out of the DI iso-form type 3 (the DI iso-form present in placenta tissues) in mice has been shown to lead to fetal growth restriction, increased perinatal mortality, and altered thyroid hormone action. Thus normal functioning of this protein is critical to fetal development. Preliminary data generated by the PI's laboratory found an inverse relationship between PBDE body burdens in human placental tissue and DI activity. Thus we propose that DI activity in placental tissue may be an important biomarker of response to PBDE exposures in pregnant women. Our central hypothesis is that increased exposure to PBDEs during pregnancy results in higher concentrations of PBDEs in placental tissues, and subsequent decreases in DI activity, affecting fetal development and birth outcomes. We will address this hypothesis through the following three specific aims: 1) Examine the correlation and partitioning of PBDEs between serum and placental tissue using banked serum and placenta tissues from an ongoing pregnancy cohort study;2) Measure inner and outer ring deiodinase (DI) activity in 200 placental tissue samples and determine the association between PBDE levels in placental tissue and DI activity;and 3) Examine the relationships between DI activity, PBDE levels, and pregnancy and birth outcomes. PUBLIC HEALTH RELEVANCE: Relevance to Public Health This research project will explore the utility of a novel thyroid biomarker in measuring human responses to brominated flame retardant chemicals, which are ubiquitous and poorly understood indoor contaminants. This proposed work will contribute to our understanding of how flame retardant exposures influence thyroid regulation, fetal development, and pregnancy outcomes. The proposed research is directly relevant to the ongoing and active policy debate regarding appropriate regulation of flame retardant chemicals.